Decreased Stathmin-1 Expression Inhibits Trophoblast Proliferation and Invasion and Is Associated with Recurrent Miscarriage

Zeng

et al. 2017

Cell Death Dis

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Peroxiredoxin (Prdx) 2 is an antioxidant protein that utilizes its redox-sensitive cysteine groups to reduce hydrogen peroxide molecules and protect cells against oxidative damage from reactive oxygen species (ROS). However, its function in trophoblasts at the maternal–fetal interface has not been clarified yet. In this study, significantly lower Prdx2 expression was found in the first-trimester villous cytotrophoblasts of patients with recurrent miscarriage (RM) than in cytotrophoblasts from healthy controls. Further, Prdx2 knockdown inhibited proliferation and increased apoptosis of trophoblast cells. The reason for this may be an increase in the level of cellular ROS after knockdown of Prdx2, which may subsequently lead to an increase in the expression of phosphorylated p53 (p-p53) and p38-MAPK/p21. Prdx2 knockdown also impaired the fusion of BeWo cells induced by forskolin. Bioinformatics analysis identified a c-Myc-binding site in the Prdx2 promoter region, and chromatin immunoprecipitation verified that c-Myc directly bound to a site in this locus. Suppression and overexpression of c-Myc resulted in reduction and increase of Prdx2 expression respectively. Furthermore, we demonstrated that c-Myc was downregulated in the first-trimester cytotrophoblasts of patients with RM, and its downregulation is also related with inhibited cell proliferation, increased apoptosis, as well as upregulated p21 expression and p-p53/p53 ratio. Our findings indicate that Prdx2 might have an important role in the regulation of trophoblast proliferation and apoptosis during early pregnancy, and that its expression is mediated by c-Myc. Thus, these two proteins may be involved in the pathogenesis of RM and may represent potential therapeutic targets.

Section: Discussionmentioning

confidence: 99%

Role of peroxiredoxin2 downregulation in recurrent miscarriage through regulation of trophoblast proliferation and apoptosis

Zeng

et al. 2017

Cell Death Dis

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“…Our results showed that, in HTR-8 cells, doxorubicin increased both mRNA and protein levels of TTP in a dose- and time-dependent manner. Previously, we had found that STMN1 expression was significantly decreased in uterine NK cells from CBA/J × DBA/2J mouse matings as compared with CBA/J × BALB/c mouse matings [42] and in patients with RSA [12], implying a link between STMN1 and p53/TTP signals.…”

Section: Discussionmentioning

confidence: 99%

“…We found that STMN1 was downregulated in the chorionic villi from patients with RSA. It is a trophoblast proliferation- and invasion-associated microtubule regulatory protein that participates in the pathogenesis of RSA [12]. …”

Section: Introductionmentioning

confidence: 99%

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Effect of the p53–tristetraprolin–stathmin-1 pathway on trophoblasts at maternal–fetal interface

et al. 2017

PLoS ONE

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ProblemTo reveal the effect of p53–tristetraprolin–stathmin-1 signaling on trophoblasts and recurrent spontaneous abortion (RSA).Method of studyStathmin-1 (STMN1), p53, and tristetraprolin (TTP) expression in paraffin-embedded villus tissue was determined using immunohistochemistry. HTR-8/SVneo cells were treated with doxorubicin to activate p53; STMN1 and TTP levels were detected by quantitative reverse transcription–PCR and western blotting. Western blotting and immunofluorescence were used to investigate STMN1 expression after TTP overexpression or knockdown in HTR-8 cells.ResultsSTMN1 was downregulated and p53 was upregulated in the villus tissue from patients with RSA. Doxorubicin decreased STMN1 expression but enhanced TTP expression in HTR-8 cells. In vitro, TTP overexpression inhibited STMN1 production; TTP knockdown promoted it. TTP downregulated STMN1 expression in trophoblasts by directly binding its 3ʹ untranslated region.ConclusionsTTP modulates trophoblast function and interacts with STMN1 and p53, and is related to pregnancy outcomes.

“…Sections were finally mounted with fluoroshield mounting medium with 4′,6‐diamidino‐2‐phenylindole (DAPI; Abcam) and then observed using a fluorescence microscope. For the BeWo cells, identification and localization of proteins were conducted using an immunofluorescence assay as previously reported 25. Rabbit anti‐adiponectin polyclonal antibody (1:50 dilution; Abcam) and E‐Cadherin rabbit monoclonal antibody (1:200 dilution; Cell Signaling Technology) were used as primary antibodies.…”

Section: Methodsmentioning

confidence: 99%

CpG Oligodeoxynucleotides Downregulate Placental Adiponectin and Increase Embryo Loss in Non‐Obese Diabetic Mice

Qin

Liu

et al. 2016

American J Rep Immunol

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ProblemCpG oligodeoxynucleotides (ODNs) can induce immunological changes in non‐obese diabetic (NOD) mice and increase embryo loss, but little is known about the mechanism. This study aimed to determine the role of adiponectin in CpG ODN‐induced pregnancy failure.Method of studyOligodeoxynucleotide 1826 was intraperitoneally injected to NOD mice, and ODN 2216, ODN 2006, and ODN 2395 were used to stimulate human trophoblast cell lines to investigate adiponectin expression patterns and its possible effects on trophoblast function.ResultsCpG ODNs downregulated adiponectin via the cJun N‐terminal kinase signaling pathway and led to increased embryo loss (from 6.9 to 33.3%). ODN 2006 impaired human trophoblast cell migration, which was successfully rescued by adiponectin treatment.ConclusionCpG ODNs decreased placental adiponectin expression in NOD mice and impaired human trophoblast function and was associated with increased embryo loss. Adiponectin may therefore play an important protective role in the prevention of bacteria‐induced pregnancy failure.